In the past year, this laboratory has studied both the short-term and long-term regulation of beta-adrenergic membrane receptors in brain. Using specific radioligand binding techniques and measurements of cyclic AMP accumulations in brain slices, we have found that exposing rat cerebral cortex slices to isoproterenol reduces the beta-adrenergic responses of the slice, a reduction explained in part by a loss of beta-adrenergic receptor binding in slice membranes. This change is rapid and can rapidly reversed by agents which depolarize brain slices. Long-term regulation of beta-adrenergic receptors was studied in the rat hippocampus after a selective, unilateral midbrain lesion destroyed the noradrenergic input to the ipsilateral brain region. Fourteen days after the lesion a slight increase in beta-adrenergic receptor binding was observed only in those animals with the most marked loss of norepinephrine. During the coming year we will study the effect of alpha-adrenergic agents on the rapid changes in beta-adrenergic receptors in brain slices and will continue to develop histochemical techniques for localizing beta-adrenergic receptors in brain. Our goal is to combine histochemical and biochemical techniques to study the fate of denervated beta-adrenergic receptors.